My LONG-TERM CAREER GOAL is to become an independent successful researcher in the field of breast cancer and mammary cancer stem cells. My deep interest in this critical translational area has developed during my recent years as a postdoctoral fellow at Stony Brook University, where I have completed several related projects, ranging from normal stem/progenitor cells to hematological malignancies to breast cancer. Yet, additional protected time will be crucial for me to become a successful independent investigator in this area, since I need to fill deficits in both, practical and theoretical knowlede, while also establishing crucial managerial skills. This K22 award will allow me to focus 100% of my time and effort to fulfill these objectives in an independent tenure-track Assistant Professor position. To fulfill my RESEARCH OBJECTIVES, I have developed a scientific Proposal aiming to investigate how HER2-positive breast cancer (HER2+ BC), one of the deadliest, is promoted by pregnancy. This connection only begins to be recognized by clinical oncologists, and my recent pioneering mouse study (Cell Death Differ 2013) and additional preliminary data indicate that one factor that potently augments pregnancy-induced HER2-positive breast cancer is a homologue of the tumor suppressor protein p53, p63. Indeed, p63 heterozygosity significantly delays tumor onset and promotes overall survival in the MMTV-ErbB2/Neu mouse model of HER2+ BC. Notably, this effect is observed in parous, but not in virgin females. Moreover, p63+/- mice also have a significant depletion of the adult mammary stem/progenitor cells termed PIMECs (parity- identified mammary epithelial cells), that are also known tumor-initiating cells for ErbB2-driven mammary tumorigenesis. Therefore, this proposal will test the OVERARCHING HYPOTHESIS that p63 promotes HER2- positive breast via augmenting tumorigenic properties of PIMECs. Specifically, AIM 1 will test whether p63 deficiency reduces tumorigenic properties of ErbB2-overexpressing PIMECs and AIM 2 will investigate whether acute genetic ablation of both p63 alleles (via the LoxP-Cre system) will completely abolish ErbB2-driven mammary tumorigenesis in vivo and also, will identify the critically involved p63 target genes. Completion of these Aims would provide rationale for future human studies to identify p63-regulated mammary cell populations implicated in parity-associated HER2+ BC and to co-target p63 effector genes to improve therapeutic outcomes of HER2+ BC patients. To implement my research project and to develop other skills necessary for future success in independent tenure-track position, I have developed a multi-modal TRAINING PLAN: (1) to acquire new knowledge in areas essential to my career goals; (2) to accomplish the Aims of my research project; and (3) to develop skills of competent lab management, interdisciplinary collaboration, successful securing of research funding etc. This plan will be accomplished through relevant coursework, guidance from my expert advisors and consultants, scientific meetings, workshops, and applied hands-on research, which altogether will enable me to establish an independent research program and apply for RO1 funding prior to the end of the K22 award. The ENVIRONMENT at Stony Brook University, its Cancer Center and the nearby Cold Spring Harbor Laboratory is ideal to support my training needs, with shared Research Core Facilities, excellent resources for early stage faculty development, and a superb cadre of world-class experts (including my advisors and consultants) in cancer biology, breast cancer, cancer stem cells, cancer genomics etc.